A phase 1/2 study of VS-6766 (RAF/MEK clamp) in combination with sotorasib (G12C inhibitor) in patients with KRAS G12C mutant non–small cell lung cancer (NSCLC) (RAMP 203).
Authors: Ramaswamy Govindan, Mark M. Awad, Shirish M. Gadgeel, Jonathan A. Pachter, Gloria Patrick, Louis J. Denis
Journal: Journal of Clinical Oncology (2022)

TPS9148 Background: KRAS is mutated (mt) in 25% of non-small cell lung cancer (NSCLC) adenocarcinoma, with KRAS G12C mt occurring in ̃13% of patients. The G12C inhibitor (G12Ci) sotorasib has recently received FDA approval for patients with KRAS G12C NSCLC. Several studies have shown that simultaneous targeting of multiple nodes in the RAS pathway may be optimal for durable pathway inhibition and response. Furthermore, acquired mutations and amplifications in the RAS pathway occur clinically upon progression on sotorasib or adagrasib. Accordingly, combination of G12Ci with a downstream blocker of the RAS pathway may be needed for more durable response. VS-6766 is a unique small molecule RAF/MEK clamp that inhibits BRAF, CRAF and MEK, enabling VS-6766 to block MEK signaling more consistently without the compensatory activation of MEK that reduces the efficacy of MEK-only inhibitors. In vitro 3D proliferation and in vivo tumor models were used to assess anti-tumor efficacy of VS-6766 ± G12Ci. In KRAS G12C mt NSCLC cell lines, VS-6766 was synergistic with both sotorasib and adagrasib in reducing tumor cell viability which correlated with deeper inhibition of RAS pathway signaling. In vivo, combination of VS-6766 with sotorasib induced strong tumor regressions in contrast to sotorasib monotherapy or sotorasib plus trametinib. Initial clinical activity of VS-6766 in KRAS G12C mt NSCLC is supported by the FRAME study [NCT03875820] results, in which 4/6 patients with KRAS G12C mt NSCLC showed tumor reduction including 1 PR. These results support the clinical evaluation of VS-6766 in combination with a G12Ci for treatment of KRAS G12C mt NSCLC. Methods: This is a Phase 1/2, multicenter, open label, dose evaluation/dose expansion study designed to evaluate the efficacy and safety of VS-6766 in combination with sotorasib in patients with KRAS G12C mt NSCLC who have not previously been treated with a KRAS G12Ci or have experienced disease progression while undergoing therapy with a KRAS G12Ci [NCT05074810]. The study will be conducted in two parts: Part A (dose evaluation) and Part B (dose expansion). Up to 3 dose levels will be evaluated in Part A to determine the Recommended Phase 2 Dose (RP2D) for Part B. Part B will assess the efficacy of the RP2D and will be conducted in 2 cohorts: patients who are G12Ci treatment naïve (cohort 1) and patients who have experienced disease progress during G12Ci therapy (Cohort 2). Patients enrolled must have histologic or cytologic evidence of NSCLC, measurable disease according to RECIST V1.1 and known KRAS G12C mutation. The study will enroll up to 121 patients with a minimum of 6 and a maximum of 12 patients in Part A and an additional 109 patients in Part B (minimum of 41 patients at RP2D stage 1 for cohort 1 and 2 or RP2D stages 1 and 2 in both cohorts). Clinical trial information: NCT05074810.